Aging and Panicogenic Response to Cholecystokinin Tetrapeptide An Examination of the Cholecystokinin System

Abstract

Older age is associated with diminished symptomatic and cardiovascular response to the panicogenic agent cholecystokinin tetrapeptide (CCK-4). We hypothesized that circulating concentrations of endogenous CCK-4 and/or CCK-8 are increased in later life, possibly due to decreased enzymatic degradation, and that this is associated with desensitization of CCK-B receptors. The study group consisted of 20 healthy subjects aged 18-30 years and 20 healthy subjects aged years. The two groups were compared on fasting basal plasma concentrations of and nonsulfated , and on binding capacity of lymphocyte CCK-B receptors. Under single-blind (to subject) conditions, subjects were then administered an intravenous bolus of placebo, followed 50 min later by an intravenous bolus of 50 g of Cholecystokinin (CCK) is a gastrin-like peptide with several molecular forms, ranging from 4 to 58 amino acid residues (Crawley and Corwin 1994). CCK was first isolated from the alimentary tract, where it has an important role in stimulating gallbladder contraction and the release of pancreatic enzymes. CCK is also abundant in the brain, where it functions as both a neurotransmitter and a neuromodulator. Two types of CCK receptor have been identified: CCK-A receptors, which are found in the viscera and some distinct brain regions, and CCK-B receptors, which are predomi- NO . 4 nantly located and widely distributed in the brain (Crawley and Corwin 1994).Intravenous administration of cholecystokinin tetrapeptide (CCK-4), a selective CCK-B agonist, produces panic attacks in humans (Bradwejn 1993). The mechanism of CCK-4-induced panic is not known. However, animal and clinical work suggests that brainstem CCK-B receptors may mediate the panicogenic effects of CCK-4, possibly through direct or indirect interaction with other neurotransmitter systems (Bradwejn 1993). Prompted by epidemiologic evidence that the prevalence and incidence of panic disorder decline in later life (Flint et al. 1996), we previously investigated the effect of aging on healthy subjects' response to CCK-4. We found that older subjects had significantly fewer and less intense symptoms of panic, shorter duration of symptoms, and less autonomic reactivity to CCK-4 compared with younger subjects (Flint et al. 1998). The purpose of the current study was to determine whether there are age-related changes in the CCK system that could account for older subjects' attenuated response to CCK-4.Studies in animals and humans have consistently found an age-related decline in sensitivity of the gallbladder and pancreas to CCK (Khalil et al. 1984(Khalil et al. , 1985a Kitani 1987, 1989;Masclee et al. 1988;Poston et al. 1988aPoston et al. , 1990Ishizuka et al. 1993). Furthermore, animal studies have found that aging is associated with a reduction in the mRNA level of pancreatic CCK-A receptors (Miyasaka et al. 1995a) and a decreased density of CCK receptors in the pancreas and gallbladder (Poston et al. 1988a,b). Very little is known about the effect of aging on brain CCK, and to our k...

Cholecystokinin Elevates Mouse Plasma Lipids

“…This CCK-induced hypercholesterolemia might be clinically important. It has been reported that bile release [30] as well as the plasma cholesterol and CCK levels [31] increase with age. It is highly possible that the age-related increase in plasma CCK is responsible for the increased bile release and hypercholesterolemia.…”

Cholecystokinin and panic disorder

“…Several studies have found that the incidence and prevalence of PD decline in later life (48). The reason for this decline is unknown, but it has been hypothesized that circulating concentrations of endogenous CCK4 and/or CCK8 are increased in later life, possibly due to decreased enzymatic degradation and that this is associated with desensitization of CCK-2 receptors (49).…”

Comorbid anxiety in late‐life depression: Relationship with remission and suicidal ideation on venlafaxine treatment

“…Time and experience are thought to aid in the development of emotional regulation (Jarvik & Russell, ). Moreover, age‐related atrophy of the locus coeruleus and other anxiety‐associated brain regions, as well as changes in peripheral physiology, are thought to attenuate anxious arousal in older individuals (Flint, ; Flint et al, ). However, aging is associated with degeneration of other brain regions that promote adaption to anxiety, for instance, the dorso‐lateral prefrontal cortex.…”